Oral administration of any therapeutic agent is always problematic relative to administration by injection. Whereas administration by injection necessarily delivers the intact therapeutic agent into the body and where need be into the direct situs where it is required, with oral administration it is critical that the therapeutic agent pass through the digestive tract and be absorbed into the body without destruction of the therapeutic agent.
With smaller drugs such as aspirin and the like, this is not a critical problem. However, with larger molecules particularly proteins denaturization is a significant problem.
As discussed in the parent application, prior attempts to administer immunologically active proteins via oral ingestion had been unsuccessful. Likewise oral administration of any therapeutic protein has been generally unsuccessful.
With such therapy if the protein administered is a foreign protein, it will have an immunological effect activating the immune system. Whereas when the protein is a native protein such as insulin (whether derived from animal sources or produced from genetically modified microorganisms) the protein does not activate the immune system but rather establishes a concentration in the blood. Other such human proteins which are not recognized by the immune system as foreign would of course include human growth factor, transforming growth factor beta. There are of course a wide variety of therapeutic proteins which are not recognized as foreign by the immune system. Such natural proteins can have a wide variety of effects on the human body.
The present invention is premised on the realization that an orally administrable therapeutic proteins can be formed by microencapsulating the protein with a coating which is insoluble under acid conditions and resistant to proteolytic digestion. Such conditions are encountered in the mammalian stomach and part of the small intestines. Preventing exposure to acid and proteolytic digestion preserves antigenic structure of the protein and its ability to immunize.
The present invention is further premised on the realization that by microencapsulating the protein under totally aqueous conditions without employing any nonaqueous solvents, the structure of the protein remains intact.
More particularly, the present invention is premised on the realization that the therapeutic proteins should be coated with an acid stable coating under totally aqueous conditions so that they can pass through the stomach without being digested and then released intact into the small intestines where they can exert their therapeutic and/or immunological activity.
In a preferred embodiment, the enteric coating is a water emulsion of ethylacrylate methylacrylic acid copolymer, or hydroxypropyl methyl cellulose acetate succinate (HPMAS).